Di-fluoro containing compounds as cysteine protease inhibitors

Abstract

The present invention is directed to compounds that are inhibitors of cysteine proteases, in particular, cathepsins B, K, L, F, and S, and are therefore useful in treating diseases mediated by these proteases. The present invention is directed to pharmaceutical compositions comprising these compounds and processes for preparing them.

1. A method for ameliorating a disease selected from neuropathic pain, Hashimoto's thyroiditis, osteoarthritis, rheumatoid arthritis, multiple sclerosis, myasthenia gravis, psoriasis, pemphigus vulgaris, Graves' disease, myasthenia gravis, systemic lupus erythemotasus, asthma, inflammatory pain or atherosclerosis in an animal mediated by Cathepsin S, which method comprises administering to the animal a pharmaceutical composition comprising a compound of Formula (I): 
       
         
           
           
               
               
           
         
         in admixture with one or more suitable excipients, 
         wherein 
         R 1  and R 2  taken together with the carbon atom to which both R 1  and R 2  are attached form cycloalkylene optionally substituted with one or two R b  independently selected from alkyl, halo, alkylamino, dialkylamino, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, alkoxycarbonyl, or aryloxycarbonyl; 
         wherein the aromatic or alicyclic ring in the groups attached to cycloalkylene is optionally substituted with one, two, or three substituents independently selected from alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryloxycarbonyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, alkoxycarbonyl, amino, monsubstituted amino, disubstituted amino, or acyl; 
         R 3  is hydrogen or alkyl; 
         R 5  is hydrogen or alkyl; 
         R 6  is aryl, optionally substituted by one, two, or three R e  independently selected from alkyl, halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, alkoxy, alkoxyalkyl, alkoxyalkyloxy, haloalkyl, haloalkoxy, oxo, cyano, nitro, acyl, cycloalkyl, cycloalkylalkyl, carboxy, alkoxycarbonyl, alkylsulfonyl, aminosulfonyl, or aminoalkyl, and further where the aromatic or alicyclic ring in R e  is optionally substituted with one, two or three R f  independently selected from alkyl, alkoxy, haloalkyl, haloalkoxy, halo, hydroxy, carboxy, cyano, nitro, aryl or cycloalkyl; 
         R 7  is haloalkyl; 
         R 8  is hydrogen, alkyl, alkoxyalkyl or haloalkyl; 
         R 22  is cycloalkyl, cycloalkylalkyl, aryl or aralkyl, wherein the aromatic or alicyclic ring in R 22  is optionally substituted with one, two, or three R d  independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, aralkyl, heteroaralkyl, amino, monsubstituted amino, disubstituted amino, or acyl; 
         Y is -alkylene-, wherein the alkylene group is optionally substituted with one to six fluoro atoms; and 
         Z is a direct bond or -alkylene-, wherein the alkylene portion is optionally substituted with one to six fluoro atoms. 
       
     
     
       2. The method of  claim 1 , wherein R 1  and R 2  together with the carbon atom to which they are attached form cycloalkylene. 
     
     
       3. The method of  claim 1 , wherein R 1  and R 2  together with the carbon atom to which they are attached form a cyclopropylene. 
     
     
       4. The method of  claim 1 , wherein R 3 , R 5  and R 8  are hydrogen; R 22  is alkyl, aryl, aralkyl, cycloalkyl or cycloalkylalkyl; Y is -alkylene-; and Z is a direct bond. 
     
     
       5. The method of  claim 1 , wherein the compound is selected from the group consisting of: